Consumers are increasingly interested in cosmetics that treat, mitigate, or delay the effects of excess lipids on their skin. The signs of excess lipids manifest themselves in an unflattering oiliness and shine to the skin due to over-production of sebum, in the “orange peel” or “cottage cheese” appearance and texture of skin affected by cellulite, or in the bulges that occur with excess subcutaneous fat. There is an active interest in the cosmetics industry to develop products that may be used to reduce the amount of lipids (anti-lipids) within the skin and thereby provide anti-oil/sebum, anti-cellulite, and anti-obesity benefits.
Sebum is an oily secretion of the sebaceous glands (sebocytes) of the skin that contains lipids (fat, triglycerides, and fatty acids), keratin, and cellular materials. Sebum normally constitutes a natural moisturizer for the epidermis maintaining its integrity. The level of sebum production varies from person to person and depends largely on sex and age. In particular, sebum production is influenced by hormones, i.e. androgens such as testosterone, and therefore occurs most prevalently in males during adolescence. During the teenage years, the complexion of the skin, i.e., the color and appearance of the skin, is oily primarily due to these hormonal changes. However, in both men and women sebum production can be stimulated by physical or emotional factors which are altered by hormones. Besides age and sex factors, sebum production is also influenced by stress, use or consumption of pharmaceuticals and drugs such as muscle stimulants and/or the presence of disease states that interfere with the autonomic nervous system such as Parkinson's, strokes, etc.
Some people exhibit hyperseborrhoeic skin characterized by an exaggerated secretion and excretion of sebum. Generally, individuals with hyperseborrhoeic skin exhibit sebum levels of greater than 200 μg/cm2 measured on the forehead. This overproduction of sebum may lead to aesthetic problems, such as oily/shiny skin or hair, acne-prone skin, enlarged pores, thickened skin, or poorer hold of makeup. Additionally, the excess sebum may act as a catalyst for acne by clogging pores leading to the formation of comedones (“blackheads” or “whiteheads”), which, when left untreated, may become inflamed and progress into acne vulgaris. Additionally, odors may be emitted as a result of excess sebum accumulation, production, or excretion.
Cellulite is a lumpy uneven type of skin texture caused by the excess accumulation of lipids (triglycerides and fatty acids) within adipocytes in subcutaneous tissues. Cellulite accumulates primarily on the buttocks, abdomen, thighs, and limbs of many women. It is considered unsightly because it gives the tissue underlying the skin an “orange peel” or “cottage cheese” look. Compressing the skin, as when sitting or crossing the legs, produces a “mattress appearance” with bulging and pitting of the fatty layer. Nodules of fat may be felt trapped within hardened connective tissue. The histology of cellulite-affected skin indicates that cellulite results from a combination of enlarged fat tissue and weak dermal structure and connective tissue septa. Excess fat accumulation increases the volume of adipocytes, which bulge into a weakened dermis (“bleeb”) to create the characteristic irregularities in the appearance of the dermal surface. Causes of cellulite include, but are not limited to, hereditary, intestinal, circulatory, lymphatic, hormonal, and lifestyle factors.
Lipids within the body, i.e. those produced by sebocytes and adipocytes, are mediated by several pathways. However, lipid metabolism appears to be controlled by peroxisome proliferator-activated receptors (“PPARs”), which form a superfamily of nuclear transcription factors. The PPARs are ligand-dependent intracellular proteins that stimulate transcription of specific genes by binding to specific DNA sequences in the nucleus following activation by the appropriate ligands. PPAR-γ activity, in particular, is governed by the binding of small lipophilic ligands, mainly fatty acids, derived from nutrition or metabolic pathways that themselves are often controlled by PPAR-γ. PPAR-γ heterodimerizes with the retinoid X receptor (RXR), leading to transactivation of genes that encode proteins involved in adipogenesis. Among the genes transactivated are several adipogenic genes including, but not limited to, fatty acid synthase (FAS), Stearoyl-CoA desaturase-1 (SCD-I), ATP-citrate lyase (ACL), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), SREBP1c, SIP, fatty aci-CoA oxidase (ACO), long and medium chain acyl-CoA dehydrogenase (LCAD and MCAD), fatty acid binding protein (FABP), fatty acid translocase (CD36), fatty acid transport protein (FATP), lipoprotein lipase (LPL), and/or alipoproteins B (ApoB). Indeed, it is believed that PPAR-γ is the centerpiece of a feed-forward pathway that favors differentiation of and energy storage by adipocytes. PPAR-γ agonists (e.g. rosiglitazone) have been shown to increase fat synthesis and storage in adipocytes; whereas lipid accumulation and adipocyte differentiation are impaired when PPAR-γ levels are reduced.
Among the genes up-regulated upon activation of PPAR-γ is FAS which encodes the enzyme FAS, necessary for the synthesis of triglycerides. FAS is one of four major enzymes involved in the fatty acid biosynthetic pathway in humans. The fatty acid biosynthetic pathway components include: acetyl-CoA carboxylase, which is the rate-limiting enzyme that synthesizes malonyl-CoA; malic enzyme, which produces NADPH; citrate lyase, which synthesizes acetyl-CoA; and FAS, which catalyzes NADPH-dependent synthesis of fatty acids from acetyl-CoA and malonyl-CoA. Inhibition of FAS interferes with fatty acid synthesis and is disclosed for example in Kuhajda, U.S. Pat. No. 5,981,575 and Orlow, et al., PCT Patent Application WO 02/087565.
SCD-I is a key lipogenic enzyme that catalyzes the synthesis of monounsaturated fatty acids. Its preferred desaturation substrates are palmitoyl-CoA and stearoyl-CoA, which are converted to palmitoleoyl-CoA and oleoyl-CoA, respectively. Oleic acid constitutes nearly half of the total fatty acids in the adipose tissue (de Vries, Am J. Clin Nutrition. 1991; 53:469-73). The absence of SCD-I leads to reduced triglyceride synthesis, decreased lipid storage, and decreased lipid export. Further, SCD-1 deficient mice have shown that loss of SCD-1 increases the expression of genes involved in fatty acid oxidation and reduces the expression of lipogenic genes. As a result of changes in gene expression, SCD-1-deficient mice have reduced body fat and increased energy expenditure and oxygen consumption (Ntambi et al. PNAS 2002; 99:1 1482-1486).
Generally, cosmetic treatments for excess lipid production provide relief from the symptoms, i.e., oiliness, enlarged pores, acne prone skin, irregular skin texture, etc., and fail to address the underlying cause. For example, the classic approach to addressing oily or shiny skin is the use of powders that provide an immediate masking effect by absorbing the excess sebum on the skin's surface. Additionally, various astringents and cleaning agents may be used to control sebum. Cellulite remedies may involve dieting to reduce fat intake, exercise to increase fat metabolism and prevent the build-up of cellulite, and massage and hydrotherapy to stimulate lymphatic drainage. However, all of these means for lipid reduction on the skin surface or within subcutaneous fat are limited, producing little sustainable visible results over extended periods of time. Astringents and cleaners may actually exacerbate the condition through a rebound effect. These means for combating sebum, cellulite, or subcutaneous fat are limited, and the need remains for additional approaches.
The Melicope plant genus includes about 150 different species of shrubs and trees in the family, which may be found in western Hawaii, tropical regions of Asia, Australia and New Zealand. Plants in the Melicope genus are commonly referred to as “Corkwood” or “Doughwood” in Australia and as “Alani” in Hawaii. We have previously shown that extracts of Melicope have an anti-inflammatory effect in U.S. Pat. No. 7,592,024, hereby incorporated by reference in its entirety for all purposes, and a restorative effect on the adipose septum, see U.S. patent application entitled “Use of adipose septum protein modulators and compositions thereof” filed contemporaneously with the current case and hereby incorporated by reference in its entirety for all purposes. However, prior to this invention it was not reported that Melicope extracts could reduce lipid accumulation and/or over-production.
There remains a need for cosmetic compositions which reduce the excess accumulation and/or over-production of lipids. It is therefore an object of the present invention to provide new compositions and methods for inhibiting excess lipid accumulation and/or over-production. It is a further object of the invention to improve the overall appearance of skin affected by excess lipids or lipid over-production, including treatment, reversal, and/or prevention of oily skin and/or hair, acne-prone skin, body odors, enlarged pores, cellulite and/or excess body fat.
The foregoing discussion is presented solely to provide a better understanding of the nature of the problems confronting the art and should not be construed in any way as an admission as to prior art nor should the citation of any reference herein be construed as an admission that such reference constitutes “prior art” to the instant application.